Since the Zika virus epidemic of 2015, there has been a surge in the number of infants in the Americas born with small heads due to brain damage that occurred when their mothers were infected during pregnancy, a condition called microcephaly.

Scientists previously thought this condition was the primary indicator of brain damage due to Zika infection, but researchers at Washington National Primate Research Center (WaNPRC) have discovered damage may still be present when head size is normal.

“Current criteria using head size to diagnose Zika-related brain issues fail to capture more subtle brain damage that can lead to significant learning problems and mental health disorders later in life,” said Kristina Adams Waldorf, MD, FACOG, a professor of obstetrics and gynecology at the UW School of Medicine who specializes in maternal and fetal infections. “We are diagnosing only the tip of the iceberg.”

In addition to Adams Waldorf, the lead researchers were Michael Gale Jr., PhD, a professor of immunology at the UW School of Medicine and an expert on how the body responds to viruses, and Lakshmi Rajagopal, PhD, an associate professor of pediatrics at the University of Washington School of Medicine and expert on newborn infectious diseases at Seattle Children’s Research Institute and UW School of Medicine.

According to the researchers, even children with a normal head size at birth may be diagnosed with serious eye injuries or late-onset microcephaly when the head fails to grow normally. Damage may also occur in children infected during early childhood and adolescence. In addition, it’s possible undetected Zika brain damage may later lead to learning disorders, psychiatric illnesses and dementia.

In the study, researchers looked for subtle changes in the brains of five fetal macaques whose mothers had been infected with the Zika virus in pregnancy. In all but one case, the researchers found no obvious fetal abnormalities with weekly ultrasounds, a medical imaging technique that is commonly used during pregnancy to assess the health of developing fetuses.

The brains of the infected fetuses, however, did grow more slowly than normal, but they remained large enough so their smaller size did not meet the criteria for Zika virus-associated microcephaly the U.S. Centers for Disease Control and Prevention uses. Under these criteria, most children (between 91 percent to 96 percent) born in the United States whose mothers were infected with Zika during the pregnancy are also not considered microcephalic. As a result, those children might not be checked regularly for Zika-related brain injury.

Magnetic resonance imaging (MRI) scans of the fetal brains, however, were abnormal in 4 of 5 of the animals. Certain areas of the brain were not growing as quickly as others. Brain regions particularly affected were areas that generate new brain cells, including the subventricular zone in the wall of the lateral ventricle, which contains the largest number of neural stem cells in the brain. Another injured part of the fetal brain was the subgranular zone of the dentate gyrus in the hippocampus, where neural stem cells play a key role in memory and learning and continue to contribute to brain health through at least adolescence.

“The study clearly shows that cells within these brain regions are highly susceptible to Zika virus infection. The findings suggest that neural stem cells within these sites, and at specific stages of development, are unable to suppress virus replication,” noted Gale.

Gale added these findings further emphasize the urgency for an effective vaccine to prevent Zika virus infections. The researchers also concluded Zika-exposed fetuses should continue to be checked for symptoms of the disease throughout their developmental years.

“All children exposed to Zika virus in utero should be followed long-term for problems with learning and development, regardless of head size at birth,” Adams Waldorf said.